Angiotensin II receptor blocking 2,3,6 substituted quinazolinones

Abstract

The invention provides novel 2,3,6-substituted quinazolinones having the formula ##STR1## wherein R 6 is ##STR2## and X, R, R 1 , R 2 , R 3 , R 4 and R 8 are described in the specification which have activity as angiotensin II (AII) antagonists.

What is claimed is: 
     
       1. A quinazolinone compound having the formula: ##STR14## wherein: R is ##STR15## X is straight or branched alkyl of 3 to 5 carbon atoms; R 6  is ##STR16## R 1  is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), 2-pyridinyl, 4-pyridinyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms); R 2  is H, or straight chain lower alkyl of 1 to 4 carbon atoms;   R 3  is H, triphenylmethyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), straight chain lower alkyl of 1 to 4 carbon atoms;   R 4  is H, straight chain lower alkyl of 1 to 4 carbon atoms, ##STR17## R 11  is lower alkyl of 1 to 3 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), --OR 7 , benzyloxy, --NH , --NHR 7 , --NR 7  R 7  ;   R 7  is lower alkyl of 1 to 3 carbon atoms;   R 8  is lower alkyl of 1 to 3 carbon atoms, phenyl; and pharmaceutically acceptable salts thereof.   
     
     
       2. The compound according to claim 1 wherein said salts are selected from potassium, sodium, calcium, magnesium or ammonium. 
     
     
       3. The compound according to claim 1 wherein X is a straight chain alkyl of 3 or 4 carbon atoms;   R 6  is ##STR18##   
     
     
       4. A quinazolinone compound having the formula: ##STR19## wherein: R 18  is ##STR20## X is straight or branched alkyl of 3 to 5 carbon atoms; R 6  is ##STR21## R 1  is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), 2-pyridinyl, 4-pyridinyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms); R 2  is H, or straight chain lower alkyl of 1 to 4 carbon atoms;   R 3  is H, triphenylmethyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), straight chain lower alkyl of 1 to 4 carbon atoms;   R 4  is H, straight chain lower alkyl of 1 to 4 carbon atoms, ##STR22## R 11  is lower alkyl of 1 to 3 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), --OR 7 , benzyloxy, --NH 2 , --NHR 7 , --NR 7  R 7  ;   R 7  is lower alkyl of 1 to 3 carbon atoms;   R 8  is lower alkyl of 1 to 3 carbon atoms, phenyl.   
     
     
       5. The compound according to claim 4 wherein X is a straight chain alkyl of 3 or 4 carbon atoms;   R 6  is ##STR23##   
     
     
       6. A pharmaceutical composition useful for treating angiotensin induced hypertension or congestive heart failure in a mammal comprising a suitable pharmaceutical carrier and an effective amount of a compound of claim 1. 
     
     
       7. A method of treating angiotensin induced hypertension in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to lower angiotensin induced hypertension. 
     
     
       8. The compound according to claim 1, CIS-3-[2-Butyl-3,4-dihydro-4-oxo-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]6-quinazolinyl]-3a,6a-dihydro-5-methyl-pyrrolo[3,4-c]pyrazole-4,6-(1H,5H)-dione. 
     
     
       9. The compound according to claim 1, (3alpha,3aalpha,6aalpha)-3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-6quinaolinyl]-2,3,3a,6a-tetrahydro-3,5-dimethyl-pyrrolo[3,4-c]pyrazole-4,6(1H,5H)-dione. 
     
     
       10. The compound according to claim 4, Cis-3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-3a,6a-dihydro-5-methyl-1-(triphenylmethyl)-pyrrolo[3,4-c]pyrazole-4,6-(1H,5H)-dione. 
     
     
       11. The compound according to claim 4, (3alpha,3aalpha,6aalpha)-3-(2-butyl-1,3-dihydro-4-oxo-6-quinazolinyl)tetrahydro-3,5-dimethyl-1-(triphenylmethyl)-pyrrolo[3,4-c]pyrazole-4,6-(1,5H)-dione. 
     
     
       12. The compound according to claim 4, (3alpha,3aalpha,6aalpha)-3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]tetrahydro-3,5-dimetyl-1-(triphenylmethyl)-pyrrolo[3,4-c]pyrazole-4,6-(1H,5H)-dione. 
     
     
       13. The compound according to claim 4, Cis-3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)3a,6a-dihydro-5-methyl-1-(triphenylmethyl)-pyrrolo[3,-c]pyrazole-4,6(1H,5H)-dione. 
     
     
       14. A method of treating congestive heart failure in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to treat congestive heart failure. 
     
     
       15. A method of antagonizing the effects of Angiotensin II in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to treat the effects of Angiotensin II.